Achieving selectivity in space and time with DNA double-strand break response and repair: molecular stages and scaffolds come with strings attached

DNA is subject to a barrage of insults arising inside and outside the cell, such as ionising radiation and attacks by reactive oxygen species. These can generate severe lesions in DNA, known as double-strand breaks. Double-strand breaks can kill cells, while their sloppy repair can lead to tumour-inducing mutations or chromosomal disruptions. Thus the ability to repair DNA damage rapidly and accurately is fundamental for cell survival and health.

DNA double-strand break repair is carried out by two distinct molecular pathways: homologous recombination and non-homologous end joining. I will use a combination of structural approaches, biophysical and computational analyses and cell imaging to investigate how reparatory proteins are brought together and assembled into complexes during non-homologous end joining. I aim to decipher the different, complementary mechanisms that coordinate this process in time and space, thereby ensuring precise and efficient DNA repair.